Identification of Early Biomarkers of Neoplastic Transformation in Mouse Tumour Models of Breast Carcinogenesis

Tomirotti, Andrea Massimiliano (2016). Identification of Early Biomarkers of Neoplastic Transformation in Mouse Tumour Models of Breast Carcinogenesis. PhD thesis The Open University.



Tumour development is not an entirely cell-autonomous process, being dependent on the ability of bystander cells, mostly of bone marrow (BM) origin, to establish a pro-tumourigenic microenvironment. We hypothesize that identification of early BM changes would confirm that BM senses the onset of a neoplastic lesion in peripheral tissues even at very early stages of carcinogenesis and that such peripheral alterations could offer the opportunity to identify key signalling molecules that may represent early biomarkers of cancerogenesis and could allow discovering novel potential therapeutic targets.

To test such hypothesis we took advantage of the MMTV-NeuT (NeuT) transgenic mouse model of mammary carcinogenesis and found that profound BM modifications in the composition and spatial arrangement of the hematopoietic populations, such as increase of immature myeloid granulocytic cells, contraction of B lymphoid pools, displacement of BM niches characterize NeuT mice with overt carcinomas in comparison to wild-type mice and that such modifications were already detectable at earlier stages of carcinogenesis, although less significant.

Genes differentially expressed in the BM between transgenic and controls with overt tumour have been used to design an ad hoc “late gene signature” that has been tested and validated in two additional breast cancer models. Early NeuT BM samples already show differentially expressed genes in comparison to controls and they are efficiently separated by the late gene signature in two clusters: those with normal/mild dysplasia in their mammary glands from those with sever dysplasia/early carcinomas. Different circulating microRNA profiles characterized early stages of tumourigenesis and BM down-regulated genes are among their predictive targets.

With an unprecedented level of integration between BM mRNA and microRNA profiles, BM immunolocalization, circulating microRNA profile and primary lesion histopathology we could demonstrate that the BM is an early sensor of incipient mammary tumour and that the alterations observed in advanced carcinomas are, at least in part, already present at early stages.

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